Heterocyclic compounds



HETERGCYCLIC COMPOUNDS Wilfred Arthur Freeman, East Barnet, David Lord Pain,

Rainham, and Ronald Slack, Chelsea, London, England, assignors to May & Baker Limited, Essex, England, a British company No Drawing. Application August 13, 1956 Serial No. 603,809

Claims priority, application Great Britain August 15, 1955 8 Claims. (Cl. 16733) This invention is for improvements in or relating to heterocycllc compounds and more particularly to new and useful nitrosopyrazoles, a process for their production tion of attachment of the one or more possible substit- I uents. More specifically, it is well known that certain l aryl 4 nitrosopyrazoles, for example i. phenyl 3:5- d1methyl-4-nitrosopyrazoleand l 4' chlorophenyl-3:5 dimethyl-4-nitrosopyrazole, are highly active fungicides finding application in the field of plant protection but it is also well known that these compounds are. severe skinirritants which readily cause dermatitis in susceptible subjects (see for example, Martin H. and Miles, I. R. W., Guide to the Chemicals Used in Crop Protection, Department of Agriculture Science Service, Dominion of Canada).

It is the object of this invention to provide new 4-nitrosopyrazoles and fungicidal compositions containing them which are highly active fungicides and which are markedly less liable to cause dermatitis in susceptible subjects coming into contact with them than hitherto used nitrosopyrazoles and fungicidal compositions containing them.

The compounds of the present invention are the lcyclopentyl 1 cyclohexyland l cycloheptyl 3:5- dimethyl 4 nitrosopyrazoles which can be represented by the conventional formula:

where R represents the cyclopentyl, cyclohexyl or cycle: heptyl radical.

These new compounds are very active fungicides and are especially valuable in the prevention and treatment of diseases of plants caused by pathogenic fungi. Consequently they may be used as foliage protectants, seed dressings or in the protection of plants against attack by mildew. In particular, they arev active against the chocolate spot fungus of broad beans (Botrytis cinerea), Sclerotinea laxa and Venturia iizaequalis. They are also active against fungi pathogenic to humans and animals and may be used in the topical treatment of infections such as ringworm caused by, for example, the following dermatophytes: Microsporum canis and T i'iciiophyton tonsurans, discoides, quinckemzum, interdigitalis, mentw grophytes, violaceum and schoenlez'ni.

Comparative experiments in which both compounds of the invention and l-aryl-4-nitrosopyraz0les have been applied repeatedly in a bland base to the shaved skin of the guinea-pig, have confirmed that the former do not hired States Patent possess to a significant degree the undesirable local toxic effects of the latter. In applicants own experience inthe laboratory severe cases of dermatitis caused .by 1'- phenyl 125 dimethyl 4 nitrosopyrazole (I. 55) and 1 4 chlorophenyl 3:5 dimethyl' 4 nitrosopyrazole (J. 49) have been encountered, while. in laboratory and field work with the compounds of'the invention no cases of dermatitis have been reported. The l-cycl'ohexylcompound of the invention constitutes the preferred compound by reason of the especially low phytotoxicity which practical experience has demonstrated it to possess.

According to a further aspect of this invention there are provided fungicidal compositions such: as dusts,.. dispersions and emulsions, which comprise one or more of the compounds of theforegoing formula in association with one or more solid or liquid diluents of. the. types commonly used in fungicidal. compositions. In the said compositions, there may also be incorporated one or more substances known to be active as fungicides, bactericides, insecticides, fertilisers or plant-growth regulating agents.

Examples of typical fungicidal compositions according to the invention are:

(a) Wettable powders comprisingthe active material dispersed in a concentration of, for example up to 50% W./w. in an inert absorbent carrier such a silicaceous earth together with an ionic or non-ionic wettingand/ or dispersing agent such as an alkali metal salt of a long chain aliphatic sulphate, a partly neutralised sulphuric acid derivative of a petroleum oil or of naturally occurring glycerides or a condensation product of. analkylene oxide with an organicacid.

(b) Self-emulsifying concentrates comprising v the active material in solution in a concentration of, for. example, up to w./v. in a suitable solvent such as: an aromatic hydrocarbon (e. g. xylene), solvent naphtha or a mineral oil together with an ionic or non-ionic wetting and/ or dispersing agent.

(c) Dusts obtained by dispersing the activev material in sufiicient of an inert absorbent carrier to form a freefiowing powder and diluting this with one or more inert carriers such as talc, diatomaceous earths, wood-flours and clays.

(d) Compositions of the active material formulated in the manner commonly employed for the. preparation of fungicidal smokes, dusts and aerosols.

The concentrated compositions described under (a) and (b) yield, on dilution with water until the concentrae tion of the active material is, for example, from 0.025% to 0.4% w./v., stable suspensions and emulsionsrespectively which are for use in the form of a spray.

According to a further feature of the invention, the aforesaid new nitrosopyrazoles are prepared by nitrosating acetylacetone and condensing the resultant isonitrosoketone CH .CO.CH(NO).COCI-I (or CH .CO.C: (NOH) .CO.CH

with cyclopentylhydrazine, cyclohexylhydrazine or cycle heptylhydrazine respectively.

The invention is illustrated by the following examples.

Example I A solution of isonitrosoacetylacetone (25.8 g.) in water ml.) was added dropwise with stirring to an icecooled solution (temp. l0 C.) of cyclohexylhydrazine hydrochloride (31 g.) in water (300 ml.). Stirring was continued for a further 2 hours when the solid nitrosopyrazole was collected and washed with water; The prod uct thus obtained is sufficiently pure for'the preparation of compositions for horticultural use but may be further purified if required by recrystallisation from ethanol or 3 petroleum-ether (B. F. 60-80 C.) to give turquoise needles, M. P. 144-145 C. a

The intermediate cyclohexylhydrazine may be prepared as follows:

Cycohexanone (49 g.) wasdissolved with cooling in Example VI a solution of hydrazine hydrate (80%: 32 ml.) in hydrochloric acid (0'. 1.16: 50 ml.). The solution was Elght repllcfite-Broad Beaflplants (V1681! f were diluted with Water (200 ml.) and hydrogenated at a presp y d h aqueous suspenswnsaf the test compounds sure of 70 lbs. per sq. in. in the presence of chloroplatinic 111 Foncentlations ranging from 150 0000373 0f the acid 10ml.) and gum-arabic (1.0 g.). Reduction 10 active compound- Plants Wen? infeted Vf/ith a was complete in 20 minutes. The residual solid was colfung s SPOIE Su5PHSi0I1 0f Bfilryfis f f and actlVltY was lected and the filtrate evaporated to dryness in vacuo. The assessed y Countlflg the numbers of Infected leaflets on combined solids may be crystallised from ethanol to' give treated and unsprayed 'P Reults are the hydrazine hydrochloride as a yellowish or colourless Pressed as the llel'celltage 0f lnhibltiofl 01516510118 y 7 solid, h f whichgval-ies f 3 to 110 C. parisonwith the unsprayed controls in the following table: according to the rate of heating.

The hydrazine hydrate-hydrochloric acid mixture may Percent inhibition of be replaced by an equivalent amount of an aqueous soigg g gg figg g g gg lution of a hydrazine salt, e. g. hydrazine hydrochloride Compound active compound or hydrazine sulphate.

Example H 0.02 0.004 0.0008

1-cyc1opentyl-37:5-dimethyl-4-nitrosopyrazo1e was pre 1-cyelohexyl-3:5-dimethyl-4-nitr0sopyrazole. 0s 4s s4 pared in a similar manner from isonitrosoacetylacetone g f g 3g 2g and cyclopentylhydrazine hydrochloride. The torquoise solid thus obtained is sufiiciently pure for many purposes but may be recrystallised from petroleum-ether (B. P. g g gggg g g fig gggfig i :5 :22, ig g sg fi gf 40-60 C.) to give blue prisms, M. 79-80 C. a at V Cyclopentylhydraz ne hydrochloride, M. P. 96-99 C., V was prepared in a manner analogous to that described in Example VII the prevmus example The activities of the test compounds against a num- Example III berof fungi pathogenic to humans and animals were deil-cycloheptyl-3zS-dimethyl-4-nitrosopyrazole, blue neet-ermmed by mcorpqratm-g tt-le con-1p ounds-m mahose ag-ar filesM. 9 90o C. v(from petroleum ether, 3 P; in a range of senatdil tions, inoculating slopes with 80 C.) was similarly prepared from isonitrosoacetyhcethe fungl undoer examination ncubatmgi i i for tone and yclohep-tylhydrazine hydrochloride. 5 days at 30 C. antdl observlng the minimal 1nh1bitory The latter, prepared in a manner analogous to that deconcentr-angl-l i 1 1 3 results obtamed scribed ab0ve,'may best be characterised as the colourless summarise mt e 0 Owing La base, B. P. l14117 C./25 mm. Hg. 40 7 Example IV (ni u i iiu fliiiiiiiii ry The fungicidal activitiesof the new nitrosopyrazoles contifgilrlzilil-inm against spores of-B0trytis cinerea, Sclerotinea laxa and rolgamsm f Venturia inaequalis were determined and compared with l-cyclo: those of 1-phenyl-3:5-dimethyl-4-nitrosopyrazole (J. 55) 55 x gg l and N-trichloromethylthio-tetrahydrophthalimide- (Captan) as follows: p V Microsporum gypxeum 2.0 1.0

Spores of thetest organisms were incubated in solutions p m -S--- 0 or suspensions of the compounds under test and after ;:8 {8 16 hours a count was made of the germination of the Candida albinanq 125.0 1.0 spores. The following table shows the minimum inhib t ggjggfgi r -"f2" 2:8 i8 itory concentrations of the test compounds: 7 Cryptococcua m0formam 1.0 0.5

Minimum We claim:

1. A member of the class consisting of the 4-nitroso- Compound pyrazoles of the formula:

V V gerprninafilion, ONC=CCH: V oH='0 N-R 1-cyc1openty1-3:5-dimethyi-4-nitrosopyrazole 0.08

l 3-5-d1n1ethyI-4-n1tr0sopyrazole 0. 008 V 5 5??? 3 33 wherein R represents a member of the class consisting of Oaptan 0.8 the cyclopentyl, cyclohexyl and cycloheptyl radicals. t 2. .1-cyclopentyl-3:5-dirnethyl-4-nitrosopyrazole. I

Example V 3. lecyclohexyl-3:S-dimethyl-4-nitrosopyrazo1e;

Thephytotoxicity of the test compounds was deteriggigggg g 15 32 233 3; i ggz ggzj g fiving mined by Spraying them on young tomato Plants s plants which comprises applying to the plant a fungicidal 0.2% aqueous suspension and assessing the damage at incomposition having as an active ingredient a member of tervals up; to tenrdays after spraying. Similar tests were the class consisting of the 4 nitrosopyrazoles of the carried out on apple trees. It was surprisingly found that. formula. V V while 1-cyclopentyl-3 :5-dirnethyl-4-nitrosopyrazole caused severe scorch and reduced growth of the tomato plants ON C OTOH3 and the corresponding cycloheptyl derivative severely CHa-C -r-B damaged the apple trees, the cyelohexyl derivative caused only very slight scorching and no reduction of growth in the tomato plants and was Without visible damaging effect upon the apple trees. For this reason, the cyclohexyl derivative is to be preferred.

nea /n15 wherein R represents a member of the class consisting of the cyclopentyl, cyclohexyl and cycloheptyl radicals.

6. The process of controlling fungus growth on living plants which comprises applying to the plant a fungicidal composition having as an active ingredient l-cyclopentyl- 3 :5-dimethyl-4-nitrosopyrazole.

7. The process of controlling fungus growth on living plants which comprises applying to the plant a fungicidal composition having as an active ingredient l-cyclohexyl- 3 :5-dimethyl-4-nitrosopyrazole.

8. The process of controlling fungus growth on living plants which comprises applying to the plant a fungicidal composition having as an active ingredient l-cycloheptyl- 3 :5-dimethyl-4-nitr0sopyrazole.

References Cited in the file of this patent UNITED STATES PATENTS Freeman June 19, 1956 OTHER REFERENCES.

McNew et aL: Chem. Abstracts, v01. 44, cols. 4183-4 1950). 

1. A MEMBER OF THE CLASS CONSISTING OF THE 4-NITROSOPYRAZOLES OF THE FORMULA:
 5. THE PROCESS OF CONTROLLING FUNGUS GROWTH ON LIVING PLANTS WHICH COMPRISES APPLYING TO THE PLANT A FUNGICIDAL COMPOSITION HAVING AS AN ACTIVE INGREDIENT A MEMBER OF THE CLASS CONSISTING OF THE 4-NITROSOPYRAZOLES OF THE FORMULA: 